Project 2 will use hypothesis-driven medicinal chemistry to optimize URMC-099 and its analogs (referred to as URMC-099C*) based on their ability to provide neuroprotection in the in vitro and in vivo models of HAND utilized by Projects 1 and 3. Through iterative cycles of optimization. Project 2 will identify a development compound for the treatment of HAND that can be advanced to an IND filing. We have previously discovered new chemical series of MLKS inhibitors by screening proprietary libraries and modified these scaffolds to provide compounds with good cellular penetration and activity in secondary assays for kinase inhibition. Subsequent compounds from this series were optimized to provide MLKS inhibitors with high levels of CNS exposure upon i.v. dosing. A prototypical advanced lead compound, URMC-099, has demonstrated efficacy during in vivo murine brain imaging experiments monitoring leukocyte trafficking, microglial activation, and preservation of synaptic architecture. We therefore propose four specific aims to complete the advancement of this chemical series to development compound status: (1) Optimize URMC-099c* to obtain potent MLKS antagonists that demonstrate appropriate CNS exposure upon oral dosing as well as efficacy in Project 1's animal models; progress promising compounds for evaluation in Project S's models of HAND; (2) Optimize the kinase inhibition profile of URMC-099c* to minimize the risk of undesirable off target activity; (S) Optimize selected lead compounds to profiles in preclinical assays acceptable for application to the NIH RAID Program for IND Supporting Studies; and (4) Devise formulations and preliminary process research synthetic methods to insure a smooth development course for the compounds, acceptance for NIH [RAID funding, and subsequent technology transfers.